The present invention relates generally to methods and materials useful in the diagnosis and treatment of infection with Human Immunodeficiency Virus (HIV). More particularly, the invention relates to immunologically active polypeptides, preferably antibodies or antibody fragments, and most preferably monoclonal antibodies, which are reactive with idiotypes of antibodies to human lymphocyte T4 protein and also reactive with the HIV virion in a manner allowing for in vitro and in vivo neutralization of HIV infectivity. Moreover, the invention relates to immunologically active polypeptides useful in vaccine compositions for developing protective responses to HIV infection.
The state of the art with respect to the epidemiology and immunology of the causative agent of AIDS in humans is well summarized in: Laurence, "The Immune System in AIDS", Scientific American, December, 1985, pp. 84-93; Gallo, "The First Human Retrovirus", Scientific American, December, 1986, pp. 88-98; Gallo, "The AIDS Virus", Scientific American, January, 1987, pp. 47-56; Levy et al., Science, 225, 840-842 (1984); "Mobilizing Against AIDS", Institute of Medicine, National Academy of Sciences, Harvard University Press (Cambridge, Mass 1986); and, Lane et al., Ann. Rev. Immunol., 3, pp. 477-500 (1985). The role of T4 surface glycoprotein (sometimes referred to as "CD4" protein or determinant) of human T lymphocytes in infection by HIV has been extensively studied as represented by Dalgleish et al., Nature, 312, pp. 763-767 (1984); Klatzman et al., Science, 312, 767-768 (1984); Klatzman et al., Science, 225, pp. 59-62 (1984); McDougal et al., J.Immunol., 135, pp. 3151-3162 (1985); and, Maddon et al., Cell, 47, pp. 333-348 (1986). See also, Marrack et al., "The T Cell and Its Receptor", Scientific American, February 1986, pp. 36-45; and, McDougal et al., Science, 231, 382-385 (1986).
It has recently been projected that soluble forms of CD4 may have therapeutic utility in treatment of HIV infection. See, Fisher et al., Nature, 331, 76-77 (1988); Hussey et al., Ibid, at pp. 78-81; Deen et al., Ibid, at pp. 82-83; and Traunecker et al., Ibid, at pp. 84-86 all of which relate to in vitro neutralization of HIV infectivity by soluble CD4. Among the potential drawbacks to the projected use of soluble CD4 therapeutic agents is the known reactivity of CD4 with class II major histocompatibility complex ("MHC") molecules present on the surface of other immune cells including B cells, macrophages and monocytes, leading to the suggestion that CD4 may need to be modified (e.g., by truncation) prior to attempted therapeutic use.
Numerous reports appear in the literature relating to the potential of antibodies to neutralize infectivity of HIV in vitro and in vivo and specifically to attempts at active immunization for the purpose of developing protective immunity See, e.g., Matthews et al., Proc. Nat'l. Acad. Sci. (USA), 83, pp. 9709-9713 (1986); Norman, "AIDS Therapy A New Push For Clinical Trials", Science, 230, pp. 1355-1358 (1985) and prior articles in this series; Newmark, Nature, 324, pp. 304-305 (1986); and notes appearing in Scientific American, February, 1987, at pages 86-88 under the heading, "AIDS: Hope . . . And Warnings", and in New Scientist, December 18, 1986, page 7, under the heading "Can Protein T Thwart The AIDS Virus . . . ?". See also, Mitsuya et al., Nature, 325, 773-778 (1987); Kennedy et al., Science, 231, 1556-1559 (1986); Chanh et al., EMBO Journal, 5(11), 3065-3071 (1986); Chanh et al., Eur. J. Immunol., 16, 1465-1468 (1986); Putney et al., Science, 4, 1392-1395 (1986); and, Matshushita et al., Abstract W.3.2, p.106, "III International Conference on Acquired Immunodeficiency Syndrome (AIDS), June 1-5, 1987.
Of interest to the background of the present invention are the published results of investigation into the immunological role of anti-idiotypes. See, e.g., Kennedy et al., "Anti-Idiotypes and Immunity", Scientific American, July, 1986, pp. 48-56; Jerne, "The Immune System", Scientific American, July, 1973, pp. 52-60; Marx, "Making Antibodies Without The Antigens", Science, 228, pp. 162-165 (1985); Finberg et al., CRC Critical Reviews in Immunoloqy, 7, 269-284 (1987); and Kennedy et al., Science, 232, pp. 220-223 (1986). See, also, Norman, supra, relating to a potential correlation between anti-HIV-immunotherapy and production of anti-idiotypic antibodies to the HIV surface proteins.
Of particular interest to the background of the present invention is the work reported by McDougal et al., J. Immunoloqy, 137, 2937-2944 (1986) wherein it was noted that: " . . . rabbit anti-idiotypic sera raised against each of four candidate CD4 monoclonal antibodies [OKT4A, OKT4D, OKT4F and Leu3a (sometimes referred to as "anti-Leu3a")] did not react with [HIV] virus or inhibit virus binding to CD4.sup.+ T cells." This notation should be compared with the recent oral presentations of Ronald C. Kennedy at the 7th Annual DNA/Hybridoma Congress, San Francisco, March 1-4, 1987, as reported in Van Brunt, Bio-Technology, 5, 421-422 (1987), and at the III International Conference on Acquired Immunodeficiency Syndrome (AIDS), Washington D.C. June 1-5, 1987, (see, Abstract TH.9.5) as reported in New Scientist June 11, 1987 at page 26. In these presentations the development of polyclonal antisera against anti-T4 antibodies was noted, as was the capacity of such antisera to recognize HIV and partially neutralize HIV infectivity in vitro. The latter presentation also mentioned preparation of monoclonal anti-idiotype antibody and this development is also described in Chanh et al., Proc. Nat'l. Acad. Sci. (USA), 84, 3891-3895 (June, 1987).
There continues to exist a substantial need in the art for new methods and materials for diagnosis for the presence of HIV particles and HIV-infected cells in biological fluid and tissue specimens and also a substantial need for new means for effecting in vivo neutralization of the infectivity of HIV and the development of vaccination procedures conferring immunological protection against HIV infection.